Working to Create Healthier Environments

Posted November 09, 2015

No one knows for sure, but experts estimate there are between a
couple of thousand and a couple of tens of thousands of commodity
chemicals in the environment. These chemicals satisfy global
markets. They are mass produced to manufacture a myriad of end-use
products, such as clothes, laundry detergents, and plastics.
Commodity chemicals are ubiquitous in the environment, and
exposures to some of them have clear effects on human health. “The
vast majority of the chemicals that we encounter in our daily life
have not been tested for safety,” said Dr. Ivan Rusyn, professor in
the Department of Veterinary Integrative Biosciences (VIBS) in the
Texas A&M College of Veterinary Medicine & Biomedical
Sciences (CVM) and member of the Texas A&M University
Interdisciplinary Faculty of Toxicology.

Moreover, until recently even chemicals already tested for
possible adverse health effects have been studied only from a
chemical perspective. That means studies generally have left out
the factor of human genetic variability. But, these chemicals in
the environment only function in the context of genetics, said Dr.
David W. Threadgill, a professor in the Department of Veterinary
Pathobiology at the CVM, a professor and the holder of the Tom and
Jean McMullin Chair of Genetics in the Department of Molecular
& Cellular Medicine at the Texas A&M Health Science Center
College of Medicine, the director of the Texas A&M Institute
for Genome Sciences and Society, and a recently named University
Distinguished Professor.

In light of possible health risks due to commodity chemicals and
genetic variability, Rusyn and Threadgill collaborate to study how
genetics influence health effects related to exposures to single
chemicals and other mixtures, like pesticides or petroleum-based
substances. “By understanding how the genetics and the environment
are interacting, we should have a much better understanding of what
actually drives disease processes,” Threadgill said.

Rusyn and Threadgill also work with VIBS professor Dr. Weihsueh
A. Chiu, a quantitative risk scientist and former branch chief at
the U.S. Environmental Protection Agency (EPA). Chiu integrates
experimental data to provide quantitative risk assessments that can
be then used for better regulatory decision making. “This
partnership between understanding genetics and understanding
toxicology is really how the science should be done today—it’s
interdisciplinary,” Rusyn said. “The data that [Threadgill] and my
lab generate are exactly what [Chiu] needs to inform regulators
much better about human health risks and environmental
exposures.”

Dr. Ivan Rusyn

Living in the Chemical World

Rusyn, a toxicologist by training, focuses on people’s
variability in their response to chemicals. That means studying not
only how exposures to chemicals in the environment can lead to
human disease, but also how different individuals might respond
differently when exposed to the same chemicals. Rusyn says
understanding variability is a key question in regulatory decision
making, especially given the lack of experimental evidence. “When
you’re trying to protect humans from exposure to a chemical,” he
said, “you need to be protecting not just an average person, but
also some of the most vulnerable or genetically susceptible.”

Rusyn explained that the EPA establishes safe exposure levels to
chemicals. Typically, these are the highest exposures to which a
person could be exposed during their lifetime without adverse
health effects. The EPA establishes these parameters using
laboratory animals that have been exposed to various doses of a
particular chemical. However, this approach uses default
assumptions to account for individual variability. “What
[Threadgill and I] are trying to do in the lab is provide
scientific information for each chemical,” Rusyn said. “Then what
[Chiu] is trying to do is create new ways in which these data can
be incorporated into quantitative risk assessment for regulatory
decision making.”

To shed light on how human variability affects adverse responses
to chemicals in the environment, Rusyn, formerly at University of
North Carolina–Chapel Hill, collaborated with scientists from the
National Institutes of Health and geneticists at UNC–Chapel Hill.
They conducted the first large-scale experiment to test effects of
environmental exposures on cells from a wide range of human
populations. In the study, they tried to capture as much genetic
diversity as exists in human population. Over 1,000 individuals
provided cell lines representing populations from Asia, Africa,
Latin America, Europe, and the United States. Then, these cells
were exposed to 180 chemicals.

“We wanted to really combine these two dimensions: genetic
variability and chemical variability,” Rusyn said. One of the
practical applications of this study was that it showed for the
first time on such a large scale the limitations of using default
assumptions in assessing chemicals’ effects on human health. The
study also showed that more experiments could be done to provide
chemical-specific information in the nexus between chemistry,
genetics, and the environment. “Right now we are regulated by ‘one
size fits all,’” Rusyn said. However, some chemicals might need
stricter regulations, while for other chemicals the same protection
could be provided with less regulation. “We cannot eliminate
chemicals,” he said. “This is important so we can help the chemical
industry, regulators, and the public to live in the chemical
world.”

Considering Genetic Variability

Severity and frequency of health effects due to chemicals in the
environment vary from individual to individual. Numerous factors,
including heritable traits, life stage, age, health history,
nutrition, and psychosocial stress, affect human variability. And
different responses to the environment result from the interactions
of these and other factors. So, how can scientists begin to
understand the connection between human variability and adverse
health effects due to chemical exposures?

Threadgill said the first step is to validate the models he has
been developing in collaboration with Rusyn, so that the scientific
community begins using them. These models will allow scientists to
better understand how mammalian systems are programmed. Ultimately,
this will determine how genetic networks drive or prevent disease
processes, how genetic variations alter these networks, and the
role of the environment in altering them.

Threadgill, a geneticist by training, creates animal- and
cell-based models to understand how human genetic variability
intersects with disease processes influenced by chemicals in the
environment. His models are then exposed to chemicals to determine
toxicity. “Considering genetic variability as a new parameter, we
can clearly show—and have shown—that the variability in response to
toxicants or drugs is far greater than what studies with a lack of
a genetics angle have shown.” His studies with Rusyn on the
toxicological effects of acetaminophen, the active ingredient in
Tylenol, have shown that individuals respond differently to it.
Even at recommended daily dosing, Threadgill explained, some
individuals develop clinical indicators of potential liver damage
due to their genotype.

Dr. David W.
Threadgill

Translating Data

Results from basic discoveries in mouse genetics and experiments
in toxicology must be translated to humans before they affect
regulation and public health protection. To do that, Chiu uses data
generated in Rusyn and Threadgill’s labs to estimate possible
adverse health effects under various scenarios.

Chiu specializes in dose response assessment, quantitative
statistical modeling, and pharmacokinetics, the science of a
chemical’s fate as it enters and eventually leaves the organism.
The body breaks down chemicals into different compounds. Analyzing
those breakdowns is important, Chiu explained, because those
breakdown products might be more toxic than the chemicals to which
an individual was originally exposed. To study that, Chiu uses
physiologically based pharmacokinetic modeling, a mathematical
model that allows him to understand how blood carries chemicals
throughout different tissues in the body.

Computer-based models allow Chiu to learn what happens to
chemicals inside the body. And to study what chemicals are doing to
cells in the body, animal-based and cell-based experiments like
those by Rusyn and Threadgill are helpful. These experiments
together help to measure different biomedical parameters, like
whether an organ is being damaged by certain chemical exposures. “I
don’t actually do the experiments, but I take those data and I
analyze them mathematically to see what the increase in severity of
effects is as you increase exposure,” Chiu said.

For example, Chiu and Rusyn have studied chemicals like
trichloroethylene, an industrial solvent commonly used in the
electronics industry and detectable in over a Dr. David W.
Threadgill thousand superfund and hazardous waste sites across the
United States. They also have studied perchloroethylene, the main
chemical used for dry cleaning. In their studies, they concluded
that trichloroethylene and perchloroethylene, both ubiquitous
environmental pollutants, are likely to be carcinogenic to humans.
Threadgill, who reached similar conclusions about trichloroethylene
in collaboration with Rusyn, followed up with another study to
analyze why some individuals seem to be uniquely sensitive to the
chemical. That information, Threadgill said, can ultimately be used
to help inform other human studies and regulators.

Dr. Weihsueh A.
Chiu

Better Decision Making

Communicating those health-related risks to the public and
decision-makers isn’t always an easy task. One of the big
challenges, Chiu said, is incorporating new data and modern animal-
and cell-based techniques. Rusyn agreed. Because it is impossible
to test thousands of chemicals on all human variations, he said
non-traditional techniques are the only way to understand human
variation and safety of chemicals. Therefore, Chiu’s role is
critical, since regulators typically struggle to digest this kind
of information. “I take those [data] into computational analysis
and translate them into something that a regulator or someone in a
state agency can use to help inform their decisions,” he said.
“It’s translating data into something that actually will have an
impact in society at large to improve protection and public
health.”

Another challenge, according to Threadgill, is to encourage the
public and decision-makers to appreciate the power of modern
techniques in genomics to improve health. “It’s a challenge in a
day and age when there seems to be a lot of public resistance to
scientific education and really making decisions on scientific
facts rather than beliefs or presumptions,” he said.

Further, regulatory decision making faces an urgent need for
modernization. United States laws classify chemicals as drugs,
pesticides, and commodity chemicals. The U.S. Food and Drug
Administration and the EPA have strict regulations for the first
two classifications. But commodity chemicals—which make up most of
the chemicals in the environment—are a different story. Those
chemicals are regulated under the outdated Toxic Substances Control
Act (TSCA) of 1976. “Chemicals are chemicals in all of those three
categories,” Rusyn said. “Because of how laws are written, the
regulatory environments are completely different, even though it
could be the same structure if it’s a drug, a pesticide, or
something that will be used in a plastic.”

Under TSCA, chemical companies aren’t required to provide
detailed information sets about a chemical’s safety. That is,
unless the EPA requires them to do so, in which case the EPA needs
to explain why chemical companies need to provide more data. Thus,
the burden of proof is on the regulators. On the contrary, other
laws, like the European Union’s Registration, Evaluation,
Authorisation and Restriction of Chemicals, enacted in 2006,
require manufacturers to prove their chemicals safe for humans and
the environment. In other words, the burden of proof is on the
chemical company.

Rusyn, Threadgill, and Chiu’s research aims to contribute to a
nationwide collaboration to modernize United States regulations.
The EPA and the National Institutes of Health alone screen
thousands of chemicals. In this massive effort, Rusyn, Threadgill,
and Chiu’s research on human variability will be crucial. “We are
the only ones trying to fill this very critical step in the
regulatory process, which is understanding or defining how much
variability there is in individuals,” Rusyn said.
Collaborating across Disciplines

With this interdisciplinary research in toxicology, genetics,
and quantitative health risk assessment, Threadgill believes Texas
A&M is poised to become an international player in the fields
of toxicology and risk assessment. Rusyn, who also emphasizes their
collaboration’s importance, said they rely on each other to tackle
this highly complex problem in public health protection and
environmental health. “That’s the concept of the One Health
initiative, where you really build a team across different spaces
to then solve complex problems,” Rusyn said. Chiu said working
across disciplines is an opportunity to make a different kind of
impact on public policy. “From academia you can make an impact by
providing new methods and data that can be disseminated and used
more widely.” He also highlighted the potential for training future
practitioners. “Whether it is in the EPA or a state agency, in
industry, or in consulting—it’s important to give people a firm
foundation not only on fundamental research, but also on how to
translate that into actionable information.”

Rusyn, Threadgill, and Chiu recently joined the Texas A&M
College of Veterinary Medicine & Biomedical Sciences as
High-Profile Faculty Hires supported by the President’s Senior
Hires Initiative and the Chancellor’s Research Initiative. To learn
more about them, visit /about-us/crih.